Adult and pediatric primary brain tumors remain very difficult clinical diseases to treat. According to the National Brain Tumor Society, only four drugs and one device have been approved to treat brain tumors in the past 30 years, despite more than 75 experimental therapeutics failing clinical development since 1998. That the mortality rates have changed little over the same time indicates that these approved treatments have provided only incremental improvements in patient survival at best. The Division of Cancer Treatment and Diagnosis (DCTD) has decided that the approach of the past three decades needs to be replaced with a new strategy to tackle these difficult diseases, which should address drug access to tumor including penetration of the blood-brain barrier (tissue pharmacokinetics), confirmed drug action on intended molecular target and its molecular consequences (pharmacodynamics), and the discovery of new molecular drug targets via analysis of genomic abnormalities and their evolution during treatment ? all in an integrated manner. DCTD envisions early clinical trials in brain tumor patients which integrate PD and tissue pharmacokinetic (PK) evaluations of investigational or approved drugs so that drug mechanism of action can be proved (or not) and the underlying reason(s) for drug treatment response or failure can be elucidated. The selection of drugs for treating brain tumors will change to the modern paradigm of precision therapeutics, in which a drug is used in a pre-selected group of patients where it can be matched to the presence of an abnormal molecular target. This project will involve development of specialized clinical grade research assay methodology and their fit-for-purpose validation using clinical biopsy specimens obtained during surgical procedures performed by neuro-oncology surgeons at the NIH Clinical Center and/or in the external cancer research community.